This proposal for a Program Project Grant (PPG) in Sudden Cardiac Death is designed to enhance our understanding of SCD by combining genetics with molecular and cellular biology and biophysics. The overall goal of the proposed research is to identify the cellular and molecular triggers that initiate fatal cardiac arrhythmias. A fundamental premise that new understandings regarding the molecular basis of normal and pathological cardiomyocyte electrical excitability will be the foundations upon which genotype-phenotype correlates combined with non-invasive testing will the foundations upon which genotype-phenotype correlations combined with non-invasive testing will be used to risk stratify patients. Major goals: 1) to elucidate the molecular basis of the triggers that initiate fatal cardiac arrhythmias that cause SCD; and 2) to establish a genotype-phenotype correlations that can be used to identify individuals at high risk for Sudden Cardiac Death who may be candidates for more aggressive therapy. The rationale for this approach is that understanding the molecular basis of the triggers for Sudden Cardiac Death will provide a mechanistic basis for risk stratification and may lead to novel therapeutic approaches. Four projects and two cores (administrative, mouse models) are proposed. Project 1 will identify variant beta- adrenergic receptors (betaAR) and ryanodine receptors (RyR) associated with increase risk of Sudden Cardiac Death. Project 2 will examine the role of adrenergic modulation of RyR/intracellular calcium release channels in initiating triggers of fetal calcium-dependent cardiac arrhythmias. Project 3 will use identified human mutations of cardiac ion channels and/or signaling molecules linked to the Long Q-T Syndrome and Brugada Syndrome as Paradigms to test the hypothesis that changes in ion channel activity may alter the configuration of the cellular action potential which contributes to changes in calcium homeostasis that, in turn, triggers arrhythmic activity. Project 4 will investigate the role of perturbations of local and global calcium signaling in initiating triggers of fatal cardiac arrhythmias. The hypothesis to be tested is that perturbations of ion channel and adrenergic mediated signaling alter calcium homeostasis in cardiomyocytes, generating triggers for fatal cardiac mediated signaling alter calcium homeostasis in cardiomyocytes, generating triggers for fatal cardiac arrhythmias. A major focus of all four projects is identification of triggers that initiate arrhythmic events. Thus, this work has the potential to determine a mechanistic basis for Sudden Cardiac Death.